1-Sulfonyl pyrrolidine derivatives

ABSTRACT

The present invention is a series of compounds that are derivatives of 1-sulfonyl-pyrrolidine and that demonstrate affinity towards metabotropic glutamate receptors. The invention further relates to medicaments containing these compounds and to a process for their preparation. The compounds possess affinity towards metabotropic glutamate receptors and are therefore useful in the treatment or prevention of acute and/or chronic neurological disorders.

[0001] This application is a divisional of U.S. patent application Ser.No. 09/880,539, filed Jun. 13, 2001.

FIELD OF INVENTION

[0002] The present invention is generally related to 1-sulfonylpyrrolidine derivitives showing affinity toward metabotropic glutamatereceptors.

BACKGROUND

[0003] In the central nervous system (CNS) the transmission of stimulitakes place by the interaction of a neurotransmitter, which is sent outby a neuron, with a neuroreceptor.

[0004] L-glutamic acid, the most commonly occurring neurotransmitter inthe CNS, plays a critical role in a large number of physiologicalprocesses. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein-coupled receptors.

[0005] At present, eight different members of these mGluR are known andof these some even have sub-types. On the basis of structuralparameters, the different influences on the synthesis of secondarymetabolites and the different affinity to low-molecular weight chemicalcompounds, these eight receptors can be sub-divided into threesub-groups:

[0006] mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong togroup II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

[0007] Ligands of metabotropic glutamate receptors belonging to thefirst group can be used for the treatment or prevention of acute and/orchronic neurological disorders such as psychosis, schizophrenia,Alzheimer's disease, cognitive disorders and memory deficits, as well aschronic and acute pain.

[0008] Other treatable indications in this connection are restrictedbrain function caused by bypass operations or transplants, poor bloodsupply to the brain, spinal cord injuries, head injuries, hypoxia causedby pregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are Huntington's chorea, amyotrophic lateral sclerosis(ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficiency functions, such as e.g. musclespasms, convulsions, migraine, urinary incontinence, nicotine addiction,opiate addiction, anxiety, vomiting, dyskinesia and depressions.

SUMMARY

[0009] The present invention is a compound of the formula

[0010] wherein

[0011] R¹ signifies hydrogen or aryl, which is unsubstituted orsubstituted by halogen;

[0012] R² signifies aryl, which is unsubstituted or substituted byhalogen or lower alkyl;

[0013] R³ signifies —OR′, cyano, halogen, N-hydroxy-amidino, —C(O)—OR,—C(O)NR′R″, —N(R′)—C(O)—R⁴, —N(R′)—S(O)₂—R, —N(R′)—C(S)—NR′″R or a 5- or6-membered heteroaryl ring containing 1 to 4 N or O heteroatoms, saidring being unsubstituted or substituted by lower alkyl or cycloalkyl;

[0014] R⁴ signifies cycloalkyl, phenyl or lower alkyl, which isunsubstituted or substituted by halogen;

[0015] R signifies lower alkyl;

[0016] R′ and R′″ signify hydrogen, lower alkyl or cycloalkyl-loweralkyl;

[0017] R″ signifies hydrogen, lower alkyl or lower alkyl substituted bya 5- or 6-membered heteroaryl ring containing from 1 to 4 N or Oheteroatoms, said ring being unsubstituted or substituted by lower alkylor cycloalkyl;

[0018] n is an integer from 0 to 5;

[0019] or its pharmaceutically acceptable salts.

[0020] It has been surprisingly found that the compounds of formula Ipossess affinity towards metabotropic glutamate receptors. Compounds offormula I are distinguished by valuable therapeutic properties.

[0021] Objects of the present invention are compounds of formula I andpharmaceutically acceptable salts thereof, racemic mixtures and theircorresponding enantiomers, the above-mentioned compounds aspharmaceutically active substances, their manufacture, medicaments basedon a compound in accordance with the invention and their production aswell as the use of the compounds in accordance with the invention in thecontrol or prevention of illnesses of the aforementioned kind, and,respectively, for the production of corresponding medicaments.

DETAILED DESCRIPTION

[0022] The present invention includes a compound of the formula

[0023] wherein

[0024] R¹ signifies hydrogen or aryl, which is unsubstituted orsubstituted by halogen;

[0025] R² signifies aryl, which is unsubstituted or substituted byhalogen or lower alkyl;

[0026] R³ signifies —OR′, cyano, halogen, N-hydroxy-amidino, —C(O)—OR,—C(O)NR′R″, —N(R′)—C(O)—R⁴, —N(R′)—S(O)₂—R, —N(R′)—C(S)—NR′″R or a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl;

[0027] R⁴ signifies cycloalkyl, phenyl or lower alkyl, which isunsubstituted or substituted by halogen;

[0028] R signifies lower alkyl;

[0029] R′ and R′″ signify hydrogen, lower alkyl or cycloalkyl-loweralkyl;

[0030] R″ signifies hydrogen, lower alkyl or lower alkyl substituted bya 5- or 6-membered heteroaryl ring containing from 1 to 4 N or Oheteroatoms, said ring being unsubstituted or substituted by lower alkylor cycloalkyl, and

[0031] n is an integer from 0 to 5;

[0032] or pharmaceutically acceptable salts thereof.

[0033] Preferred compounds of formula I include a compound wherein R¹ ishydrogen; R² is aryl unsubstituted or substituted by halogen or loweralkyl; R³ and n are as defined above. An additional preferred compoundincludes a compound wherein R² is p-tolyl and n is 3. Yet an additionalpreferred compound includes R³ as N(R′)—C(O)—R⁴, or 5- or 6-memberedheteroaryl groups containing 1 to 4 heteroatoms selected independentlyfrom each other from N or O, which are unsubstituted or substituted bylower alkyl or cycloalkyl, and R⁴ is as defined above.

[0034] A further preferred compound has the structure

[0035] wherein R³ and n are as above; and wherein R⁵ is hydrogen,halogen or lower alkyl. Additionally, compound I-A wherein R³ is —OR′,N-hydroxy-amidino, —C(O)NR′R″ or —N(R′)—C(O)—R⁴; R⁵ is halogen and n is2 or 3 is preferred. Compound I-A is also preferred when R³ is OR′; R⁵is ethyl; R′ is as above and n is 1. Another preferred compound offormula I-A includes R³ being a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 heteroatoms selected independently from eachother from N or O, which is unsubsituted or substituted by lower alkylor cycloalkyl with n as an integer between 0 and 5.

[0036] Another preferred compound of the present invention has thestructure

[0037] wherein R³ and n are as above.

[0038] A compound of formula I-B when R³ is an unsubstituted 5-memberedheteroaryl group containing from 1 to 4 heteroatoms selectedindependently from each other from N or O is also preferred. Yet anotherpreferred compound of formula I-B includes R³ as an unsubstituted5-membered heteroaryl group containing from 1 to 4 nitrogen atoms and nis 0, 1 or 2. A compound of formula I-B is also preferred when theheteroaryl group includes at least one oxygen and n is 0, 1 or 2 or whenn is 3, 4 or 5. An additional preferred compound of formula I-B includesR³ being a substituted 5-membered heteroaryl group containing 1 to 4heteroatoms selected independently from each other from N or O; the5-membered heteroaryl group containing from 1 to 4 nitrogen atoms with nas 0, 1 or 2; or the case where the substituted 5-membered -heteroarylgroup contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5. Anadditional preferred compound of formula I-B includes R³ being asubstituted 5-membered heteroaryl group containing 1 to 4 heteroatomsselected from N or O and containing at least one N and at least one Owherein n is 0, 1 or 2; or when n is 3, 4, or 5.

[0039] Yet another preferred compound of formula I-B includes R³ beingselected from —C(O)—OR, —C(O)NR′R″, cyano, halogen, N-hydroxy-amidino,—N(R′)—C(O)—R⁴, —C(O)—OR, —N(R′)—S(O₂)—R and —N(R′)—C(S)—NR′″R, whereinR′, R″, R′″, R⁴ and R are as defined above.

[0040] Another preferred compound of formula I has the structure

[0041] wherein R³ and n are as defined above. Another preferred compoundof formula I-C includes R³ being —N(R′)—C(O)—R⁴; wherein R⁴ and R′ areas defined above with n being 0, 1 or 2 or additionally when n is 3, 4or 5. Yet another preferred compound of formula IV includes R³ being—N(R′)—C(O)—R⁴; wherein R⁴ and R′ are as defined above; and n is 3, 4 or5. A further preferred compound of formula I-C includes R³ being—C(O)NR′R″, wherein R′ and R″ are as defined above.

[0042] An additional preferred compound of formula IV includes R³ being5- or 6-membered heteroaryl groups containing from 1 to 4 heteroatomsselected independently from each other from N or O, which areunsubstituted or substituted by lower alkyl or cycloalkyl.

[0043] One further preferred compound of formula IV includes R³ being asubstituted 5-membered heteroaryl group with n being 0, 1 or 2, or withn being 3, 4 or 5. Another preferred compound of formula I-C includes R³being an unsubstituted 5-membered heteroaryl group with n being 0, 1 or2 or the case when n is 3, 4 or 5. One more preferred compound offormula I-C includes R³ being —OR′ with R′ is as above and n is 0, 1 or2, or 3, 4 or 5.

[0044] Preferred compounds of formula I in the scope of the presentinvention are those, in which R³ signifies 5- or 6-membered heteroarylgroups containing from 1 to 4 heteroatoms selected independently fromeach other from N or O, which are optionally substituted by lower alkylor cycloalkyl.

[0045] Especially preferred are compounds of formula I, wherein theheteroaryl group is selected from imidazole, pyrazole, [1,2,4]triazole,[1,2,4]oxadiazole or tetrazole, which is optionally substituted by loweralkyl or cycloalkyl.

[0046] The following are examples of such compounds:

[0047](2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-3-methyl-[1,2,4]oxadiazole,

[0048](2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H-tetrazole,

[0049](2RS,5RS)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-2H-tetrazole,

[0050](2RS,5RS)-5-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1-methyl-1H-tetrazole,

[0051](2R,5S)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole,

[0052](2R,5S)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole,

[0053](2RS,5RS)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole,

[0054](2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole,

[0055](2RS,5SR)-3-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole,

[0056](2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole,

[0057](2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole,

[0058](2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole,

[0059](2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-tetrazole,

[0060](2RS,5SR)-3-cyclopropyl-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,2,4]oxadiazole,

[0061](2RS,5SR)-1-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-[1,2,4]triazole,

[0062](2R,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole,

[0063](2S,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole,

[0064](2S,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole,

[0065](2S,5S)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole,

[0066](2RS,5RS)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole,

[0067](2RS,5RS)-2-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2H-tetrazole,

[0068](2S,5S)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole,or

[0069](2S,5S)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.

[0070] Further preferred compounds of formula I are those, wherein theheteroaryl group is selected from [1,3,4]oxadiazole or oxazole, which isoptionally substituted by lower alkyl or cycloalkyl.

[0071] The following are examples of such compounds:

[0072](2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}[1,3,4]oxadiazole,

[0073](2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole,

[0074](2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-oxazole,

[0075](2RS,5RS)-2-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}[1,3,4]oxadiazole,or

[0076](2RS,5RS)-2-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-[1,3,4]oxadiazole.

[0077] Further preferred are compounds of formula I, in which

[0078] R³ signifies —N(R′)—C(O)—R⁴ and

[0079] R⁴ signifies cycloalkyl or lower alkyl, which is optionallysubstituted by halogen.

[0080] The following are examples of such compounds:

[0081] (2RS,5SR)-cyclopropanecarboxylic acid[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide,

[0082] (2SR,5SR)-cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide,

[0083] (2S,5S)-cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide,

[0084](2SR,5SR)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide,

[0085](2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-propionamide,

[0086](2RS,5RS)-N-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-acetamide,

[0087](2RS,5RS)-N-{5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-acetamide,

[0088](2S,5S)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide,

[0089](2RS,5RS)-2,2,2-trifluoro-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide,or

[0090](2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-isobutyramide.

[0091] Also preferred are compounds of formula I, in which

[0092] R³ signifies —OR′ and

[0093] R′ signifies hydrogen or methyl.

[0094] The following are examples of such compounds:

[0095](2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol,

[0096](2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol,

[0097](2RS,5SR)-2-(4-fluoro-phenyl)-5-(2-methoxy-ethyl)-1-(toluene-4-sulfonyl)-pyrrolidine,

[0098](2RS,5RS)-2-(4-fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine,

[0099](2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol,or

[0100](2S,5S)-2-(4-fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.

[0101] Further preferred are compounds of formula I, in which

[0102] R³ signifies —C(O)NR′R″ and

[0103] R′ signifies hydrogen or lower alkyl and

[0104] R″ signifies hydrogen, lower alkyl or lower alkyl substituted bya 5- or 6-membered heteroaryl group containing 1 to 4 heteroatomsselected from N or O, which is optionally substituted by lower alkyl orcycloalkyl.

[0105] The following are examples of such compounds:

[0106](2RS,5RS)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoicacid amide, or

[0107](2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.

[0108] Compounds of formula I, in which

[0109] R³ signifies —N(R′)—S(O)₂—R and

[0110] R signifies lower alkyl and

[0111] R′ signifies hydrogen, lower alkyl or lower alkyl substituted bya 5- or 6-membered heteroaryl group containing 1 to 4 heteroatomsselected from N or O, which is optionally substituted by lower alkyl orcycloalkyl, are also preferred.

[0112](2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-methanesulfonamideis an example of such a compound.

[0113] The invention embraces all stereoisomeric forms in addition tothe racemates.

[0114] The term “lower alkyl” used in the present description denotesstraight-chain or branched saturated hydrocarbon residues with 1 to 6carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl,ethyl, n-propyl, i-propyl, t-butyl and the like.

[0115] The term “cycloalkyl” denotes a saturated carbocyclic groupcontaining from 3 to 7 carbon atoms, preferred are cyclopropyl andcyclopentyl.

[0116] The term “cycloalkyl-lower alkyl” denotes a lower alkyl residueas defined above which is substituted by a cycloalkyl group as definedabove, preferred is cyclopropylmethyl.

[0117] The term “halogen” denotes fluorine, chlorine, bromine andiodine.

[0118] The term “aryl” means the monovalent aromatic carbocyclic radicalconsisting of one individual ring, or one or more fused rings in whichat least one ring is aromatic in nature. Preferred aryl groups arephenyl or naphthyl.

[0119] The term “heteroaryl” means the monovalent aromatic cyclicradical incorporating one or more heteroatoms. The term “5- or6-membered heteroaryl rings containing from 1 to 4 N or O heteroatoms”embraces furyl, pyrrolyl, 1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl,1H-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl,1H-[1,2,4]triazolyl, 4H-[1,2,4]triazolyl, 1H-[1,2,3]triazolyl,2H-[1,2,3]triazolyl, 4H-[1,2,3]triazolyl, [1,2,4]oxadiazolyl,[1,3,4]oxadiazolyl, [1,2,3]oxadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl,[1,2,3,4]oxatriazolyl, [1,2,3,5]oxatriazolyl, 1H-pentazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl and their dihydro derivatives. Theheteroaryl ring is optionally substituted by lower alkyl or cycloalkyl.

[0120] Preferred are the following 5-membered heteroaryl rings:1H-imidazolyl, 1H-pyrazolyl, 1H-[1,2,4]triazolyl, [1,2,4]oxadiazolyl,4,5-dihydro-[1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl, oxazolyl,1H-tetrazolyl and 2H-tetrazolyl.

[0121] Preferred 6-membered heteroaryl groups are pyridyl or pyrimidyl.

[0122] The compounds of formula I and their pharmaceutically acceptablesalts can be manufactured by reacting a compound of the formula

[0123] with a compound of formula

[0124] to obtain a compound of formula

[0125] and, if desired,

[0126] converting a functional group of R³ in a compound of formula Iinto another functional group,

[0127] and if desired,

[0128] converting a compound of formula I into a pharmaceuticallyacceptable salt.

[0129] Compounds of formula I may also be obtained directly by simplyexchanging the functional group at position R³ by another functionalgroup.

[0130] In accordance with the invention, an appropriately substitutedcompound of formula II, for example methyl(2RS,5SR)-5-(4-fluorophenyl)-1-pyrrolidine-2-carboxylate, is reactedwith a suitable compound of formula III, for example toluene-4-sulfonylchloride and triethylamine (see Scheme 1). R¹, R³ and n have thesignificance given earlier. The reaction according to known methods iscarried out at room temperature within 16 hours in an inert solvent, forexample in dichloromethane.

[0131] A compound of formula II is prepared by reacting a suitablecompound of formula V with diethyl acetaminomalonate (IV) followed byhydrogenation on platinum oxide according to Scheme 2 or, for the casewhen R′ is H (see Example 84), DL-proline methyl ester can be used asstarting material.

[0132] A stereoselective synthesis of a compound of formula II can beachieved by reacting optically pure N-Boc-pyroglutamate with(4-fluoro-phenyl)magnesium bromide according to the methods described inTetrahedron Letters 34, 6317-6320, 1999, J. Med. Chem. 39, 2594-2608,1996 and Tetrahedron: Asymmetry 10, 2245-2303, 1999.

[0133] Scheme 3 shows how prolongation of the side chain starting with acompound of formula Ia, for example (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester (Example 1), can be achieved. For instance, afterreduction with lithium aluminium hydride to the corresponding alcohol,mesylation and nucleophilic substitution by cyanide compounds of formulaIc having a side chain with 2 C-atoms are obtained. Compounds of formulaIa1 containing 3 C-atoms in the side chain are prepared by oxidation ofthe alcohol to the aldehyde VII followed by Wittig reaction andhydrogenation.

[0134] Tetrazolyl derivatives of formula If (e.g. Examples 27, 39, 40,49, 50) can be prepared by a 1,3-dipolar addition of sodium azide to anitrile of formula Ic1. The nitrile is preferably obtained by convertingthe ester group of a compound of formula Ia2 into the amide anddehydrating the amide with phosphorus oxychloride.Methyl-1,2,4-Triazolyl derivatives of formula Ig (e.g. examples 26, 69,70) can be manufactured by addition of methylhydrazine to the nitrile.The cyano group of a compound of formula Ic1 can further be hydrogenatedto the corresponding amine, which may be acylated with a suitableacylchloride to obtain a compound of formula Ie (e.g. examples 9, 15,16). The acylation is preferably carried out with pyridine indichloromethane. An overview of these reactions is given in Scheme 4below. R⁴ has the significance given earlier.

[0135] The formation of a 1,2,4-oxadiazolyl ring can be achieved bycondensation of an acid of formula VIII with N-hydroxy-acetamidine asfollows: a solution of the acid and 1,1′-carbonyl-diimidazole is stirredin DMF at room temperature for 2 h. N-hydroxy-acetamidine is then addedand the reaction mixture is heated to 80° C. for 16 h. After evaporationand solvation in acetic acid the reaction mixture is heated under refluxconditions for 2 h and after purification using known methods a compoundof formula Ih (e.g. Example 25) is obtained (see Scheme 5).

[0136] 1,2,4-Oxadiazolyl derivatives of formula Ij (e.g. Example 13) canbe manufactured from the nitrile of formula Ic1 by reaction withhydroxylamine hydrochloride to obtain the carboxamidine Ii, which iscondensed with acetic acid in DMF in the presence of1,1′-carbonyl-diimidazole to form the 1,2,4-oxadiazolyl ring.

[0137] The hydroxyl group of a compound of formula Ib1 can be methylatedby known methods to obtain a compound of formula Im or substituted by ahalogen atom. For example, reaction with thionylchloride yields thecorresponding chloralkyl derivative (Ik). The halogen atom can furtherbe substituted with a cyclic amine, for example 1,2,4-triazol (seeExample 82), with the help of sodium hydride at 0° C. The product, acompound of formula Il, is purified by known methods. In Scheme 6, Xsignifies, independently from each other, a N-atom or a C-atom.

[0138] The pharmaceutically acceptable salts can be manufactured readilyaccording to methods known per se and taking into consideration thenature of the compound to be converted into a salt. Inorganic or organicacids such as, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid or citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methanesulphonic acid, p-toluenesulphonic acid and the like aresuitable for the formation of pharmaceutically acceptable salts of basiccompounds of formula I. Compounds which contain the alkali metals oralkaline earth metals, for example sodium, potassium, calcium, magnesiumor the like, basic amines or basic amino acids are suitable for theformation of pharmaceutically acceptable salts of acidic compounds.

[0139] The compounds of formula I and their pharmaceutically acceptablesalts possess, as already mentioned above, affinity towards metabotropicglutamate receptors (group 1 mGlu receptors) and can be used for thetreatment or prevention of acute and/or chronic neurological disorders,such as psychosis, schizophrenia, Alzheimer's disease, cognitivedisorders and memory deficits, as well as acute and chronic pain. Othertreatable indications are restricted brain function caused by bypassoperations or transplants, poor blood supply to the brain, spinal cordinjuries, head injuries, hypoxia caused by pregnancy, cardiac arrest andhypoglycaemia. Further treatable indications are Alzheimer's disease,Huntington's chorea, ALS, dementia caused by AIDS, eye injuries,retinopathy, idiopathic parkinsonism or parkinsonism caused bymedicaments as well as conditions which lead to glutamate-deficientfunctions, such as e.g. muscle spasms, convulsions, migraine, urinaryincontinence, nicotine addiction, psychoses, opiate addiction, anxiety,vomiting, dyskinesia and depression.

[0140] The pharmacological activity of the compounds was tested usingthe following method: cDNA encoding rat mGlu 1a receptor was transientlytransfected into EBNA cells using a procedure described by E.-J.Schlaeger and K. Christensen (Transient gene expression in mammaliancells grown in serum-free suspension culture; Cytotechnology, 15: 1-13,1998). [Ca²⁺]i measurements were performed on mGlu 1a transfected EBNAcells after incubation of the cells with Fluo-3 AM (0.5 μM finalconcentration) for 1 hour at 37° C. followed by 4 washes with assaybuffer (DMEM supplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]imeasurements were done using a fluorometric imaging plate reader (FLIPR,Molecular Devices Corporation, La Jolla, Calif., USA). When compoundswere evaluated as antagonists they were tested against 10 μM glutamateas agonist.

[0141] The inhibition (antagonists) or activation (agonists) curves werefitted with a four parameter logistic equation giving EC₅₀, IC₅₀, andHill coefficient using the iterative non linear curve fitting softwareOrigin (Microcal Software Inc., Northampton, Mass., USA).

[0142] The compounds of the present invention are group 1 mGlu receptoragonists. All of the compounds of the invention show activities, asmeasured in the assay described above, of 10 μM or less, typically 1 μMor less, and ideally of 0.3 μM or less.

[0143] In the table below are shown some specific activity data: ExampleNo. Compound name EC₅₀ (μM) 4(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4- 4.40sulfonyl)-pyrrolidine-2-carbonitrile 5(2RS,5SR)-2-chloromethyl-5-(4-fluoro-phenyl)- 1.401-(toluene-4-sulfonyl)-pyrrolidine 16 (2RS,5SR)-cyclopropanecarboxylicacid[5-(4- 0.21 fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide 21(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4- 0.63sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl- [1,2,4]oxadiazole 39(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4- 0.36sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H- tetrazole 64(2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4- 0.20sulfonyl)-pyrrolidin-2-yl]-propan-1-ol 77(2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1- 0.16(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}- methanesulfonamide 87(RS)-cyclopropanecarboxylic acid{3-[1- 0.98(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}- amide 101(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1- 1.47(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2H- tetrazole 116(2S,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4- 0.22sulfonyl)-pyrrolidin-2-yl]-propyl}-1H- imidazole 123(2RS,5RS)-2-{3-[5-(4-fluoro-phenyl)-1- 1.28(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}- 4,6-dimethyl-pyrimidine137 (2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4- 1.24sulfonyl)-pyrrolidin-2-yl]-[1,3,4]oxadiazole 143(2RS,5RS)-2-{4-[5-(4-fluoro-phenyl)-1- 0.35(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}- 2H-tetrazole

[0144] The compounds of formula I or the pharmaceutically acceptablesalts thereof can be used as medicaments, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. However, the administration can also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

[0145] The compounds of formula I and pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatine capsules. Suitablecarriers for soft gelatine capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like; depending onthe nature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, for example, water, polyols,sucrose, invert sugar, glucose and the like. Adjuvants, such asalcohols, polyols, glycerol, vegetable oils and the like, can be usedfor aqueous injection solutions of water-soluble salts of compounds offormula I, but as a rule are not necessary. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

[0146] In addition, the pharmaceutical preparations can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants and the like. They canalso contain still other therapeutically valuable substances.

[0147] As mentioned earlier, medicaments containing a compound offormula I or a pharmaceutically acceptable salt thereof and atherapeutically inert excipient are also an object of the presentinvention, as is a process for the production of such medicaments whichcomprises bringing one or more compounds of formula I orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenical dosage formtogether with one or more therapeutically inert carriers.

[0148] The dosage can vary within wide limits and will, of course, befitted to the individual requirements in each particular case. Ingeneral, the effective dosage for oral or parenteral administration isbetween 0.01-20 mg/kg/day, with a dosage of 0.1-0 mg/kg/day beingpreferred for all of the indications described. The daily dosage for anadult human being weighing 70 kg accordingly lies between 0.7-1400 mgper day, preferably between 7 and 700 mg per day

[0149] Finally, as mentioned earlier, the use of compounds of formula Iand of pharmaceutically acceptable salts thereof for the production ofmedicaments, especially for the control or prevention of acute and/orchronic neurological disorders of the aforementioned kind, is also anobject of the invention.

EXAMPLE 1(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid Methyl Ester

[0150] a) Diethyl acetamido[2-(4-fluorobenzoyl)-ethyl]malonate

[0151] To a stirred solution of diethyl acetaminomalonate (4.34 g, 0.02mol) in EtOH (30 ml) was added at room temperature sodium ethanolate(1.46 g, 20.4 mmol) and subsequently 3-chloro-4′-fluoro-propiophenone(3.73 g, 0.02 mol). The reaction mixture was heated under refluxconditions for 5 h, poured onto ice-water (70 ml), acidified (25 ml 3Nsulfuric acid) and extracted with ethyl acetate (2×100 ml). The combinedorganic layers were washed with brine (70 ml), dried (MgSO₄) andevaporated to give a brown oil (7.95 g). Crystallization from ethylacetate/hexane yielded diethylacetamido[2-(4-fluorobenzoyl)-ethyl]malonate (5.72 g, yield 78%) as anoff-white solid, m.p. 73° C.

[0152] b) Methyl (RS)-2-(4-fluorophenyl)-1-pyrroline-5-carboxylate

[0153] A stirred solution of diethylacetamido[2-(4-fluorobenzoyl)-ethyl]malonate (5.72 g, 15.6 mmol) inconc. hydrochloric acid (45 ml) was heated under reflux conditions for15 h, filtered and evaporated. Subsequently hydrochloric acid in MeOH(3N, 30 ml) was added and the solution stirred at room temperature for20 h. The reaction mixture was evaporated, sat. NaHCO₃ solution wasadded (50 ml) and the aqueous phase was extracted with ethyl acetate(2×100 ml). The combined organic layers were washed with brine (70 ml),dried (MgSO4) and evaporated to give methyl(RS)-2-(4-fluorophenyl)-1-pyrroline-5-carboxylate (2.3 g, yield 67%) asa pale brown oil, MS: m/e=221 (M⁺).

[0154] c) Methyl(2RS,5SR)-5-(4-fluorophenyl)-1-pyrrolidine-2-carboxylate

[0155] Hydrogenation of methyl(RS)-2-(4-fluorophenyl)-1-pyrroline-5-carboxylate (2.3 g, 10.4 mmol) onplatinum oxide (260 mg) in MeOH (120 ml) for 3 h at room temperatureyielded methyl (2RS,5SR)-5-(4-fluorophenyl)-1-pyrrolidine-2-carboxylate(2.27 g, yield 98%) as a light brown oil, MS: m/e=224.2 (M+H⁺).

[0156] d)(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid Methyl Ester

[0157] To a stirred solution of methyl(2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate (2.27 g, 10.2mmol) and triethylamine (2.13 ml, 15.3 mmol) in dichloromethane (60 ml)was added at 0° C. toluene-4-sulfonyl chloride (2.32 g, 12.2 mmol). Themixture was stirred at RT for 16 h, evaporated, dissolved in water (50ml) and extracted with dichloromethane (2×40 ml). The combined organiclayers were washed with water (40 ml), brine (40 ml), dried (MgSO₄) andevaporated. The crude product was purified by crystallization fromdiethyl ether/hexane to give the title compound, off-white solid, m.p.91° C. and MS: m/e=378.3 (M+H⁺).

EXAMPLE 2(2RS,5SR)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol

[0158] Reduction of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT,aqueous work-up and crystallization from diethyl ether/hexane yieldedthe title compound, white solid, m.p. 82° C. and MS: m/e=350 (M+H⁺).

EXAMPLE 3(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid Amide

[0159] A solution of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester (1.3 g, 3.44 mmol) in MeOH (75 ml) and ammoniumhydroxide solution (50 ml, 25%) was stirred at room temperature for 72h. The volume of the solution was reduced to 50 ml and water (150 ml)was added. The title compound precipitated as a white solid (0.95 g,yield 76%), m.p. 137° C. and MS: m/e=363.1 (M+H⁺)

EXAMPLE 4(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile

[0160] A stirred mixture of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid amide (1.15 g, 3.17 mmol) and phosphorus oxide chloride (8 ml) washeated for 5 min under reflux conditions. Aqueous work-up andcrystallization from ethyl acetate/hexane yielded the title compound asa light brown solid (0.9 g, yield 82%), m.p. 128° C. and MS: m/e=344(M⁺).

EXAMPLE 5(2RS,5SR)-2-Chloromethyl-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0161] A stirred mixture of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol(1.25 g, 3.58 mmol) and thionyl chloride (2 ml) was heated for 4 h at80° C. aqueous work-up and crystallization from ethyl acetate/hexaneyielded the title compound as an off-white solid (1.12 g, yield 85%),m.p. 130° C. and MS: m/e=367 (M⁺).

EXAMPLE 6(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid (pyridin-3-yl-methyl)-amide Hydrochloride

[0162] a)(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid

[0163] A solution of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester (4.35 g, 11.5 mmol) in 1N potassium hydroxide solution(100 ml) was stirred at room temperature for 17 h. Aqueous work-upyielded(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid (4.05 g, yield 97%) as a white solid, m.p. 166° C.

[0164] b)(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicChloride

[0165] To a stirred suspension of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid (4.05 g, 11.1 mmol) in toluene (60 ml) was added thionyl chloride(1.21 ml, 16.7 mmol) and the mixture was stirred at 80° C. for 1.5 h.Evaporation of the solvent yielded(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicchloride as a light brown solid.

[0166] c)(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid (pyridin-3-yl-methyl)-amide Hydrochloride

[0167] To a stirred and cooled (0° C.) solution of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicchloride (764 mg, 2 mmol) in dichloromethane (30 ml) was added pyridine(0.16 ml, 2 mmol) and 3-picolylamine (0.18 ml, 1.8 mmol). The reactionmixture was stirred at room temperature for 22 h. Aqueous work-up,formation of the hydrochloride (3N MeOH/HCl) and crystallization(diethyl ether) yielded the title compound (0.69 g, yield 70%) as awhite solid, m.p. 186° C. and MS: m/e=454.5 (M+H⁺).

EXAMPLE 7(2RS,5SR)-5-(4-Fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine

[0168] To a stirred suspension of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile(0.74 g, 2.15 mmol) in EtOH (25 ml) was added potassium carbonate (0.89g, 6.45 mmol) and hydroxylamine hydrochloride (0.30 g, 4.30 mmol). Thereaction mixture was heated under reflux conditions for 18 h, the formedprecipitate collected, washed with dichloromethane/methanol. The organicsolvents were evaporated and the crude product purified by columnchromatography on silica gel (ethyl acetate/hexane 3:2). Crystallizationfrom diethyl ether/methanol yielded the title compound (0.31 g, yield38%) as a white solid, m.p. 217° C. and MS: m/e=378.3 (M+H⁺).

EXAMPLE 8(2RS,5SR)-2-(4-Fluoro-phenyl)-5-methoxymethyl-1-(toluene-4-sulfonyl)-pyrrolidine

[0169] To a stirred and cooled (0° C.) solution of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanolin THF (10 ml) was added sodium hydride (147 mg, 3.66 mmol, 60%) and thereaction mixture was stirred at room temperature for 1 h. Subsequentlymethyl iodide (0.34 ml, 5.5 mmol) was added at 0° C. and stirring wascontinued for 3 h at room temperature. Aqueous work-up andcrystallization from ethyl acetate/hexane yielded the title compound asa white solid (0.53 g, yield 79%), m.p. 152° C. and MS: m/c=364.3(M+H⁺).

EXAMPLE 9(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-acetamide

[0170] a)(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamine

[0171] Hydrogenation of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile(1.22 g, 3.54 mmol) in 7N MeOH/NH₃ at RT with Ra—Ni as catalyst yielded(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamine(1.06 g, yield 86%) as a pale yellow oil.

[0172] b)(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-acetamide

[0173] Acetylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as a white solid, m.p.117° C. and MS: m/e=391.2 (M+H⁺).

EXAMPLE 10(2RS,5SR)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrile

[0174] Reaction of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol(2.15 g, 6.15 mmol) and methanesulfonyl chloride (0.57 ml, 7.38 mmol) inaccordance with the general method of example 1d yielded thecorresponding(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanesulfonate(2.60 g, 99%), which was subsequently heated with potassium cyanide(0.61 g, 9.43 mmol) in EtOH/water (95:5; 130 ml) under reflux conditionsfor 24 h. Aqueous work-up and column chromatography on silica gel (ethylacetate/hexane 2:3) gave the starting material (1.02 g, 47%) and thetitle compound (0.64 g, yield 29%) as an off-white solid, m.p. 116° C.and MS: m/e=359.2 (M+H⁺).

EXAMPLE 11(2RS,5SR)-[1-(4-Ethyl-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-methanol

[0175] The title compound, pale yellow oil, MS: m/e=363 (M⁺) wasprepared in accordance with the general methods of example 1d and 84afrom methyl (2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate and4-ethyl-benzenesulfonyl chloride and subsequent reduction of methyl(2RS,5SR)-5-(4-fluoro-phenyl)-1-(4-ethyl-benzenesulfonyl)-pyrrolidine-2-carboxylatewith lithium aluminum hydride according to the general method of example2.

EXAMPLE 12(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine

[0176] The title compound, off-white solid, m.p. 84° C. and MS:m/e=390.3 (M+H⁺) was prepared in accordance with the general method ofexample 7 from(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrile.

EXAMPLE 13(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-[1,2,4]oxadiazole

[0177] A solution of acetic acid (0.11 ml, 1.99 mmol),1,1′-carbonyl-diimidazole (0.32 g, 1.99 mmol) in DMF (12 ml) was stirredat room temperature for 2 h and subsequently(2RS,5SR)-5-(4-fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine(0.50 g, 1.32 mmol) was added. The reaction mixture was stirred at 80°C. for 16 h and evaporated. Acetic acid (10 ml) was added and thestirred mixture was heated under reflux conditions for 2 h. Aqueouswork-up, column chromatography on silica gel (ethyl acetate/hexane 1:1)and crystallization from ethyl acetate/hexane yielded the title compound(0.36 g, yield 68%) as a white solid, m.p. 115° C. and MS: m/e=246.1(M+H⁺).

EXAMPLE 14(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,2,4]oxadiazole

[0178] A stirred solution of(2RS,5SR)-5-(4-fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine(0.49 g, 1.3 mmol) in triethyl orthoformiate (20 ml) was heated underreflux conditions for 2.5 h. Aqueous work-up, column chromatography onsilica gel (toluene/ethyl acetate 4:1) and crystallization from ethylacetate/hexane yielded the title compound (0.11 g, yield 22%) as a whitesolid, m.p. 165° C. and MS: m/e=387 (M⁺).

EXAMPLE 15(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-propionamide

[0179] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as a white solid, m.p.142° C. and MS: m/e=405.4 (M+H⁺).

EXAMPLE 16 (2RS,5SR)-Cyclopropanecarboxylic acid[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide

[0180] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as a white solid, m.p.154° C. and MS: m/e=417.3 (M+H⁺).

EXAMPLE 17(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-propionamide

[0181] Hydrogenation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrileaccording to the general method of example 9a and subsequent acylationof the corresponding(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethylaminein accordance with the general method of example 6c yielded the titlecompound as a colorless oil, MS: m/e=419.4 (M+H⁺).

EXAMPLE 18(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-benzamide

[0182] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as a light brown solid,m.p. 60° C. and MS: m/e=467.3 (M+H⁺).

EXAMPLE 19 (2RS,5SR)-Cyclopropanecarboxylic acid{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-amide

[0183] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethylamineaccording to the general method of example 6c and column chromatographyon silica gel yielded the title compound as a colorless oil, MS: m/e431.5 (M+H⁺).

EXAMPLE 20(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-acetamide

[0184] Acetylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as a white solid, m.p.124° C. and MS: m/e=405.4 (M+H⁺).

EXAMPLE 21(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,2,4]oxadiazole

[0185] The title compound, pale yellow oil, MS: m/e=416.3 (M+H⁺) wasprepared in accordance with the general method of example 13 from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidineand acetic acid.

EXAMPLE 22(2RS,5SR)-5-Cyclopropyl-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole

[0186] The title compound, pale yellow oil, MS: m/e=442.3 (M+H⁺) wasprepared in accordance with the general method of example 13 from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidineand cyclopropyl-carboxylic acid.

EXAMPLE 23(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole

[0187] The title compound, colorless oil, MS: m/e=402.0 (M+H⁺) wasprepared in accordance with the general method of example 14 from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine.

EXAMPLE 24(2RS,5SR)-5-Phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic AcidAmide

[0188] The title compound, white solid, m.p. 130° C. and MS: m/e=300.1(M+H⁺) was prepared in accordance with the general method of example 3from (2RS,5SR)-5-phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester, which was prepared in accordance with the generalmethod of example 1d from (2RS,5SR)-5-phenyl-pyrrolidine-2-carboxylicacid methyl ester and toluene-4-sulfonyl chloride.

EXAMPLE 25(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-3-methyl-[1,2,4]oxadiazole

[0189] The title compound, off-white solid, m.p. 128° C. and MS:m/e=401.2 (M⁺) was prepared in accordance with the general method ofexample 13 from(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid and N-hydroxy-acetamidine.

EXAMPLE 26(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-[1,2,4]triazole

[0190] To a freshly prepared solution of hydrochloric acid in EtOH (10ml) was added at 0° C.(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile(0.50 g, 1.45 mmol), the reaction mixture was stirred at roomtemperature for 1.5 h and evaporated. The light brown solid (0.65 g) wasdissolved in EtOH (10 ml), methylhydrazine (86.9 mg, 1.89 mmol) andtriethylamine (0.51 ml, 3.63 mmol) were added and the mixture wasstirred at room temperature for 2 h. The reaction mixture wasevaporated, subsequently dissolved in formic acid (10 ml), stirred atroom temperature for 0.5 h and heated under reflux conditions for 1.5 h.Evaporation, aqueous work-up, column chromatography on silica gel (ethylacetate) and crystallization from ethyl acetate/hexane yielded the titlecompound (0.37 g, yield 64%) as a white solid, m.p. 160° C. and MS:m/e=400 (M⁺).

EXAMPLE 27(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2-methyl-2H-tetrazole

[0191] a)(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole

[0192] To a stirred solution of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile(0.70 g, 2.03 mmol) in DMF (25 ml) was added at room temperature sodiumazide (0.40 g, 6.10 mmol) and triethylamine hydrochloride (0.42 g, 3.05mmol) and the reaction mixture was stirred at 120° C. for 6 h. Themixture was poured in water (100 ml), acidified (2 N HCl) and the formedsolid was collected to give(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole(0.73 g, yield 93%) as an off-white solid, m.p. 150° C.

[0193] b)(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2-methyl-2H-tetrazole

[0194] To a stirred solution of(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole(0.72 g, 1.86 mmol) in acetone (30 ml) was added at room temperaturepotassium carbonate (0.51 g, 3.72 mmol) and methyl iodide (0.23 ml, 3.72mmol) and the reaction mixture was heated under reflux conditions for 3h. Aqueous work-up, column chromatography on silica gel (ethylacetate/hexane 2:3) and crystallization from ethyl acetate/hexaneyielded the title compound (0.44 g, 59%) as a white solid, m.p. 150° C.and MS: m/e=402.4 (M+H⁺). As second product of this reaction(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-tetrazole(0.26 g, yield 35%) was obtained as a white solid, m.p. 186° C. and MS:m/e 402.4 (M+H⁺).

EXAMPLE 283-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-4,5-dihydro-[1,2,41oxadiazole (Mixture of Diastereoisomers; 2,5-cis)

[0195] To a stirred suspension of(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine(0.4 g, 1.06 mmol) in EtOH (12.5 ml)/water (10 ml) was addedacetaldehyde (4.2 ml, 74.4 mmol) and the reaction mixture was heatedunder reflux conditions for 8 h. Evaporation of the solvent, aqueouswork-up yielded the crude product (0.5 g) as a colorless oil. Furtherpurification by column chromatography on silica gel (ethylacetate/hexane 3:2) and crystallization from ethyl acetate/hexane gavethe title compound as a white solid, m.p. 68° C. and MS: m/e=404.4(M+H⁺).

EXAMPLE 29(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide

[0196] a)(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxaldehyde

[0197] To a stirred solution of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol(8.12 g, 23.2 mmol) in dichloromethane (150 ml) was added triethylamine(16.2 ml, 116 mmol). To the cooled solution (0° C.) was added dropwiseover a period of 15 min pyridine-SO₃-complex (18.3 g, 116 mmol)dissolved in DMSO (75 ml) and the reaction mixture was stirred for 1 hat 0° C. Aqueous work-up yielded(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxaldehyde(8.0 g, yield 99%) as a light brown oil.

[0198] b)(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicAcid Methyl Ester

[0199] To a cooled (0° C.) and stirred suspension of sodium hydride(1.29 g, 32.2 mmol; 60%) in THF (60 ml) was added over a period of 20min trimethyl phosphonoacetate (5.31 ml, 36.8 mmol) in THF (40 ml).After 30 min a solution of(2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxaldehyde(8.0 g, 23.0 mmol) in THF (40 ml) was added dropwise over a period of 25min and the reaction mixture was subsequently stirred at 55° C. for 2 h.Aqueous work-up and further purification by column chromatography onsilica gel (toluene/ethyl acetate 9:1) yielded the product as acolorless oil (5.77 g, 62%), which was subsequently dissolved in MeOH(200 ml) and hydrogenated at room temperature on Pd-C (10%, 0.6 g) overa period of 1.5 h to give(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester (5.35 g, yield 92%) as a colorless oil.

[0200] c)(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide

[0201] The title compound, off-white solid, m.p. 136° C. and MS: m/e391.2 (M+H⁺) was prepared in accordance with the general method ofexample 3 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester.

EXAMPLE 30(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-3-methyl-1,2,4]oxadiazole

[0202] The title compound, white solid, m.p. 91° C. and MS: m/e=430.5(M⁺) was prepared in accordance with the general method of example 13from N-hydroxy-acetamidine and(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid, which was prepared in accordance with the general method ofexample 6a from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester.

EXAMPLE 31(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile

[0203] The title compound, white solid, m.p. 86° C. and MS: m/e=373.1(M+H⁺) was prepared in accordance with the general method of example 4from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.

EXAMPLE 32(2SR,5SR)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0204] Hydrogenation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrileaccording to the general method of example 9a and subsequent acetylationof the corresponding(2SR,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylaminein accordance with the general method of example 6c yielded the titlecompound as a colorless oil, MS: m/e=419.3 (M+H⁺).

EXAMPLE 33 (2SR,5SR)-Cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide

[0205] Acylation of(2SR,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=445.5 (M+H⁺).

EXAMPLE 34(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-propionamidine

[0206] The title compound, off-white solid, m.p. 134° C. and MS:m/e=406.4 (M+H⁺) was prepared in accordance with the general method ofexample 7 from(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile.

EXAMPLE 35(2RS,5SR)-5-Cyclopropyl-3-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole

[0207] The title compound, pale brown oil, MS: m/e=455 (M⁺) was preparedin accordance with the general method of example 13 from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-propionamidineand cyclopropyl-carboxylic acid.

EXAMPLE 36(2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,2,4]oxadiazole

[0208] The title compound, pale brown oil, MS: m/e=430.1 (M+H⁺) wasprepared in accordance with the general method of example 13 from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-propionamidineand acetic acid.

EXAMPLE 37 (2RS,5SR)-Cyclopentanecarboxylic Acid[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide

[0209] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamineaccording to the general method of example 6c and crystallization fromethyl acetate/hexane yielded the title compound as an off-white solid,m.p. 147° C. and MS: m/e=445.3 (M+H⁺).

EXAMPLE 38(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2,2-dimethyl-propionamide

[0210] Acylation of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methylamineaccording to the general method of example 6c and crystallization fromhexane yielded the title compound as a white solid, m.p. 128° C. and MS:m/e=433.4 (M+H⁺).

EXAMPLE 39(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H-tetrazole

[0211] The title compound, colorless oil, MS: m/e=416.1 (M+H⁺) wasprepared in accordance with the general method of example 27a/b from(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrile.

[0212] A second product of this reaction was(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-1-methyl-1H-tetrazole,colorless oil, MS: m/e=416.3 (M+H⁺).

EXAMPLE 40(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole

[0213] The title compound, colorless oil, MS: m/e=430.4 (M+H⁺) wasprepared in accordance with the general method of example 27a/b from(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile.

[0214] A second product of this reaction was(2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole,colorless oil, MS: m/e=430.1 (M+H⁺).

EXAMPLE 41(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl-propionamide

[0215] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=433.4 (M+H⁺).

EXAMPLE 42(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2,2-dimethyl-propionamide

[0216] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=461.3 (M+H⁺).

EXAMPLE 43 (2RS,5RS)-Cyclopentanecarboxylic Acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide

[0217] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=473.3 (M+H⁺).

EXAMPLE 44(2RS,5RS)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol

[0218] Reduction of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT,aqueous work-up and crystallization from EE/hexane yielded the titlecompound, white solid, m.p. 93° C. and MS: m/e=378.2 (M+H⁺).

EXAMPLE 45(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile

[0219] Transformation of(2RS,5RS)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olaccording to the general method of example 10 yielded the titlecompound, off-white solid, m.p. 74° C. and MS: m/e=386 (M⁺).

EXAMPLE 46(2RS,5RS)-N-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-acetamide

[0220] Hydrogenation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrileaccording to the general method of example 9a and subsequent acetylationof the corresponding(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butylaminein accordance with the general method of example 6c yielded the titlecompound as a colorless oil, MS: m/e=433.4 (M+H⁺).

EXAMPLE 47 (2RS,5RS)-Cyclopropanecarboxylic acid14-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-amide

[0221] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=459.5 (M+H⁺).

EXAMPLE 48(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoicAcid Amide

[0222] Transformation of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olin accordance with the general method of example 29a-c gave the titlecompound as an off-white semisolid, MS: m/e=419.3 (M+H⁺).

EXAMPLE 49(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-2H-tetrazole

[0223] The title compound, light yellow solid, m.p. 107° C. and MS:m/e=444.3 (M+H⁺) was prepared in accordance with the general method ofexample 27a/b from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile.

EXAMPLE 50(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-tetrazole

[0224] The title compound, white solid, m.p. 153° C. and MS: m/e=444.3(M+H⁺) was prepared in accordance with the general method of example27a/b from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile.

EXAMPLE 51(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanenitrile

[0225] The title compound, white solid, m.p. 79° C. and MS: m/e=401.2(M+H⁺) was prepared in accordance with the general method of example 4from(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoicacid amide.

EXAMPLE 52(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine

[0226] The title compound, white foam, MS: m/e=420.3 (M+H⁺) was preparedin accordance with the general method of example 7 from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile.

EXAMPLE 53(2RS,5RS)-N-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-acetamide

[0227] Hydrogenation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanenitrileaccording to the general method of example 9a and subsequent acetylationof the corresponding(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentylaminein accordance with the general method of example 6c yielded the titlecompound as a colorless oil, MS: m/e=447.4 (M+H⁺).

EXAMPLE 54(2RS,5RS)-5-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1-methyl-1H-tetrazole

[0228] The title compound, white solid, m.p. 120° C. and MS: m/e=458.4(M+H⁺) was prepared in accordance with the general method of example27a/b from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanenitrile.

[0229] A second product of this reaction was(2RS,5RS)-5-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2-methyl-2H-tetrazole,light yellow solid, m.p. 77° C. and MS: m/e=458.4 (M+H⁺).

EXAMPLE 55(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-pentanamidine

[0230] The title compound, white foam, MS: m/e=434.5 (M+H⁺) was preparedin accordance with the general method of example 7 from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanenitrile.

EXAMPLE 56(2RS,5SR)-N-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-acetamide

[0231] a)(2RS,5SR)-1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylicAcid Methyl Ester

[0232] Reaction of(2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate with4-chloro-benzenesulfonyl chloride according to the general procedure Idyielded(2RS,5SR)-1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylicacid methyl ester as an off-white solid, MS: m/e=398 (M⁺).

[0233] b)(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-methanol

[0234] Reduction of(2RS,5SR)-1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylicacid methyl ester with LiAlH₄ according to the general method of example2 gave(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-methanolas a colorless oil, MS: m/e=370 (M⁺).

[0235] c)(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-acetonitrile

[0236] Transformation of(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-methanolaccording to the general procedure of example 10 yielded(2RS,5SR)-[-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-acetonitrileas a light yellow oil, MS: m/e=379 (M⁺).

[0237] d)(2RS,5SR)-N-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-acetamide

[0238] Hydrogenation of(2RS,5SR)-[-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-acetonitrileaccording to the general method of example 9a and subsequent acetylationof the corresponding(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-ethylaminein accordance with the general method of example 6c yielded the titlecompound as a white solid, m.p 103° C. and MS: m/e=425.3 (M+H⁺).

EXAMPLE 57 (2RS,5SR)-Cyclopropanecarboxylic Acid{2-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-amide

[0239] Acylation of(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-ethylamineaccording to the general method of example 6c yielded the title compoundas a white solid, m.p. 80° C. and MS: m/e=451.3 (M+H⁺).

EXAMPLE 58(2R,5S)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol

[0240] a)(2R,5S)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicAcid Ethyl Ester

[0241] Reaction of ethyl(2R,5S)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate [prepared from(S)-ethyl N-Boc-pyroglutamate and (4-fluoro-phenyl)magnesium bromideaccording to: a) Tetrahedron Letters 34 (1993) 6317-6320. b) Journal ofMedicinal Chemistry 39 (1996) 2594-2608. and c) Tetrahedron: Asymmetry10 (1999) 2245-2303.] and toluene-4-sulfonyl chloride according to thegeneral method of example 1 d yielded(2R,5S)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid ethyl ester as a white solid, m.p. 78° C., [α]_(D) ²⁰=−36.9°(c=1.0151 in chloroform) and MS: m/e=392.2 (M+H⁺).

[0242] The(2S,5R)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid ethyl ester [white solid, m.p. 78° C., [α]D²⁰=+34.7° (c=1.0709 inchloroform) and MS: m/e=392.2 (M+H^(t))] was prepared from ethyl(2S,5R)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate.

[0243] b)(2R,5S)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol

[0244] Reduction of(2R,5S)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid ethyl ester according to the general method of example 2 gave thetitle compound as a white solid, m.p. 140° C., [α]_(D) ²⁰=135.3°(c=1.0642 in chloroform) and MS: m/e=350.2 (M+H⁺).

[0245](2S,5R)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol:white solid, m.p. 140° C., [α]_(D) ²⁰=+135.9° (c=1.0789 in chloroform)and MS: m/e=350.1 (M+H⁺).

EXAMPLE 59(2R,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide

[0246] The title compound, light yellow foam, [α]_(D) ²⁰=−124.4°(c=1.0865 in chloroform) and MS: m/e=391.1 (M+H⁺), was prepared inaccordance with the general method of example 29 from(2R,5S)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol.

[0247](2S,5R)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide:light yellow foam, [α]_(D) ²⁰=+124.2° (c=1.1010 in chloroform) and MS:m/e=391.2 (M+H⁺).

EXAMPLE 60(2S,5S)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0248] a)(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile

[0249] Reaction of(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamidein accordance with the general method of example 4 yielded(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrileas a light brown oil, [α]_(D) ²⁰=95.0° (c=1.0972 in chloroform) and MS:m/e=372 (M⁺).

[0250](2S,5R)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile:light brown oil, [α]_(D) ²⁰=+94.4° (c=1.0955 in chloroform) and MS:m/e=372 (M⁺).

[0251] b)(2S,5S)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0252] The title compound, colorless semisolid, [α]_(D) ²⁰=−70.7°(c=1.1206 in chloroform) and MS: m/e=419.3 (M+H⁺) was prepared asdescribed for the racemic compound (example 32) from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile.

[0253](2R,5R)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide:colorless semisolid, [α]_(D) ²⁰=+71.6° (c=1.1446 in chloroform) and MS:m/e=419.3 (M+H⁺).

EXAMPLE 61 (2S,5S)-Cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide

[0254] The title compound, crystallized from oil, white, [α]_(D)²⁰=−61.7° (c=1.0926 in chloroform) and MS: m/e=445.4 (M+H⁺) was preparedas described for the racemic compound (example 33) from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile.

[0255] (2R,5R)-Cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide:crystallized from oil, white, [α]_(D) ²⁰=+60.2° (c=1.0764 in chloroform)and MS: m/e=445.3 (M+H⁺).

EXAMPLE 62(2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole

[0256] The title compound, crystallized from oil, white, [α]_(D)²⁰=58.6° (c=1.0632 in chloroform) and MS: m/e=430.2 (M+H⁺) was preparedin accordance with the general method of example 27 from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile.

[0257](2S,5R)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole:crystallized from oil, white, [α]_(D) ²⁰=+59.3° (c=1.0812 in chloroform)and MS: m/e=430.3 (M+H⁺).

EXAMPLE 63(2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole

[0258] The title compound, crystallized from oil, light yellow, [α]_(D)²⁰=−97.6° (c=1.0795 in chloroform) and MS: m/e=430.2 (M+H⁺) was preparedin accordance with the general method of example 27 from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile(see example 62, regioisomer).

[0259](2S,5R)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole:crystallized from oil, light yellow, [α]_(D) ²⁰=+100.7° (c=1.0749 inchloroform) and MS: m/e=430.1 (M+H⁺).

EXAMPLE 64(2S,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol

[0260] The title compound, white solid, m.p. 96° C., [α]_(D) ²⁰=−97.1°(c=1.0723 in chloroform) and MS: m/e=378.2 (M+H⁺)] was prepared inaccordance with the general method of example 44 from(2S,5R)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester [see example 59: colorless oil, [α]_(D) ²⁰=−96.4°(c=1.0992 in chloroform) and MS: m/e=406.1 (M+H⁺)].

[0261](2R,5R)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol:white solid, m.p. 96° C., [α]_(D) ²⁰=+97.5° (c=1.1287 in chloroform) andMS: m/e=378.2 (M+H⁺);[(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester: colorless oil, [α]_(D) ²⁰=+94.0° (c=1.0868 inchloroform) and MS: m/e=406.1 (M+H⁺)].

EXAMPLE 65(2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionamide

[0262] a)(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionicAcid Methyl Ester

[0263] Reaction of(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-methanolin accordance with general method of example 29a/b yielded(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionicacid methyl ester as a colorless oil, MS: m/e=426.1 (M+H⁺).

[0264] b)(2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionamide

[0265] The title compound, light brown solid, m.p. 114° C. and MS:m/e=411 (M⁺) was prepared in accordance with the general method ofexample 3 from(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionicacid methyl ester.

EXAMPLE 66(2RS,5RS)-N-{3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0266] a)(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionitrile

[0267] Reaction of(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionamideaccording to general method of example 4 gave(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionitrileas a white solid, m.p. 108° C. and MS: m/e=393 (M⁺).

[0268] b)(2RS,5RS)-N-{3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0269] Hydrogenation of(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-propionitrileaccording to the general method of example 9a and subsequent acetylationof the corresponding(2RS,5SR)-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidine-2-yl]-propylaminein accordance with the general method of example 6c yielded the titlecompound as a white solid, m.p. 49° C. and MS: m/e=439.3 (M+H⁺).

EXAMPLE 67(2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propan-1-ol

[0270] Reduction of(2RS,5SR)-3-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionicacid methyl ester in accordance with general method of example 2 yieldedthe title compound as a colorless oil, MS: m/e=498 (M⁺).

EXAMPLE 68(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyramide

[0271] A mixture of(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile(2.0 g, 5.17 mmol) and conc. sulfuric acid (20 ml) was stirred at RT for17 h, poured into 150 ml ice/water and extracted with ethyl acetate(2×100 ml). The combined organic layers were washed with water (100 ml),dried (MgSO₄) and evaporated to give the title compound as a white foam,MS: m/e=404 (M⁺).

EXAMPLE 69(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole

[0272] The title compound, colorless oil, MS: m/e=443.2 (M+H⁺), wasprepared in accordance with the general method of example 26 from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrileand methylhydrazine.

EXAMPLE 70(2RS,5RS)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole

[0273] The title compound, colorless oil, MS: m/e=443.2 (M+H⁺), wasprepared in accordance with the general method of example 26 from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrileand methylhydrazine.

EXAMPLE 71(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-[1,2,4]oxadiazole

[0274] a)(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricAcid

[0275] A stirred mixture of(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyramide(1.57 g, 3.88 mmol) and conc. hydrochloric acid (30 ml) was heated underreflux conditions for 3 h, poured into ice/water (150 ml) and extractedwith ethyl acetate (2×100 ml). The combined organic layers were washedwith brine (2×80 ml), dried (MgSO₄) and evaporated. The crude productwas purified by crystallization from ethyl acetate/hexane to give(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid (1.45 g, yield 92%) as an off-white solid, m.p. 87° C. and MS:m/e=404.4 (M−H⁺).

[0276] b)(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-[1,2,4]oxadiazole

[0277] The title compound, white solid, m.p. 91° C. and MS: m/e=443 (M⁺)was prepared in accordance with the general method of example 13 fromN-hydroxy-acetamidine and(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid.

EXAMPLE 72(2RS,5RS)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-[1,2,41oxadiazole

[0278] The title compound, colorless oil, MS: m/e=430.3 (M+H⁺) wasprepared in accordance with the general method of example 14 from(2RS,5RS)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine.

EXAMPLE 73(2RS,5SR)-5-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole

[0279] The title compound, colorless gum, MS: m/e=450.2 (M+H⁺) wasprepared in accordance with the general method of example 27a/b from(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(4-chloro-benzenesulfonyl)-pyrrolidin-2-yl]-propionitrile.

[0280] A second product of this reaction was(2RS,5RS)-5-{4-[5-(4-fluoro-phenyl)-1-(4-chloro-benzenesulfonyl)-pyrrolidin-2-yl]-butyl}-2-methyl-2H-tetrazole,white solid, m.p. 122° C. and MS: m/e=450.2 (M+H⁺).

EXAMPLE 74(2RS,5SR)-2-(4-Fluoro-phenyl)-5-(2-methoxy-ethyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0281] Methylation of(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethan-1-olaccording to the general method of example 8 yielded the title compoundas colorless oil, MS: m/e=378.2 (M+H⁺).

EXAMPLE 75(2RS,5SR)-3-Cyclopropyl-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole

[0282] The title compound, white solid, m.p. 129° C. and MS: m/e=456.4(M⁺) was prepared in accordance with the general method of example 13from N-hydroxy-cyclopropane-carboxamidine and(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid.

EXAMPLE 76(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-benzamide

[0283] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=481.4 (M+H⁺).

EXAMPLE 77(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-methanesulfonamide

[0284] Reaction of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylaminewith methanesulfonyl chloride according to the general method of example1d yielded the title compound as a white solid, m.p. 123° C. and MS:m/e=455.3 (M+H⁺).

EXAMPLE 78(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole

[0285] The title compound, white solid, m.p.=145° C. and MS: m/e=429.5(M+H⁺), was prepared in accordance with the general method of example 26from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrileand methylhydrazine.

EXAMPLE 79(2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole

[0286] The title compound, colorless oil, MS: m/e=429.5 (M+H⁺), wasprepared in accordance with the general method of example 26 from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrileand methylhydrazine.

EXAMPLE 80(2RS,5RS)-2,2,2-Trifluoro-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0287] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=473.1 (M+H⁺).

EXAMPLE 81(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-thiourea

[0288] Reaction of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamine(0.5 g, 1.33 mmol) with methyl isothiocyanate (117 mg, 1.59 mmol) indichloromethane (10 ml) at RT and purification of the crude product bycolumn chromatography on silica gel (ethyl acetate) yielded the titlecompound (0.48 g, yield 80%) as a white foam, MS: m/e=450.4 (M+H⁺).

EXAMPLE 82(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole

[0289] a)(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0290] Reaction of(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olaccording to the general method of example 5 yielded(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineas a light brow solid,

[0291] m.p.=81° C. and MS: m/e=396.3 (M+H⁺).

[0292] b)(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole

[0293] To a stirred solution of 1,2,4-triazol (105 mg, 1.52 mmol) in DMF(15 ml) was added at 0° C. sodium hydride (61 mg, 1.52 mmol; 60%-disp.).The mixture was stirred at RT for

[0294] 1 h, cooled to 0° C. and(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine(0.50 g, 1.26 mmol) was added. The reaction mixture was stirred at RTfor 3 h and at 50° C. for 16 h, poured into ice/water (70 ml) andextracted with dichloromethane (2×100 ml). The combined organic layerswere washed with water (70 ml) and brine (70 ml), dried (MgSO₄) andevaporated. The crude product was purified by column chromatography onsilica gel (ethyl acetate) to yield the title compound (0.47 g, yield87%) as a colorless oil, MS: m/e=429.5 (M+H⁺).

EXAMPLE 83(2RS,5RS)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0295] Methylation of(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olaccording to the general method of example 8 yielded the title compoundas light yellow oil, MS: m/e=392.2 (M+H⁺).

EXAMPLE 84(RS)-N-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0296] a) (RS)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic AcidMethyl Ester

[0297] Reaction of DL-proline methylester with toluene-4-sulfonylchloride according to the general procedure of example 1d yielded(RS)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl esteras a white solid, m.p.=93° C. and MS: m/e=283 (M⁺).

[0298] b) (RS)-[1-(toluene-4-sulfonyl)-pyrrolidine-2-yl]-methanol

[0299] Reduction of (RS)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester with LiAlH₄ according to the general method of example2 gave (RS)-[1-(toluene-4-sulfonyl)-pyrrolidine-2-yl]-methanol as acolorless oil, MS: m/e=255 (M⁺).

[0300] c) (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic AcidMethyl Ester

[0301] Reaction of(RS)-[1-(toluene-4-sulfonyl)-pyrrolidine-2-yl]-methanol in accordancewith general method of example 29a/b yielded(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methylester as an off-white semisolid, MS: m/e=312.1 (M+H⁺).

[0302] d) (RS)-3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide

[0303] (RS)-3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide,light brown oil, MS: m/e 297.1 (M+H⁺) was prepared in accordance withthe general method of example 3 from(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methylester.

[0304] e) (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile

[0305] Reaction of(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide accordingto general method of example 4 gave(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionitrile as a whitesemisolid, MS: m/e=278 (M⁺).

[0306] f)(RS)-N-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide

[0307] Hydrogenation of(RS)-[1-(toluene-4-sulfonyl)-pyrrolidine-2-yl]-propionitrile accordingto the general method of example 9a and subsequent acetylation of thecorresponding (RS)-[1-(toluene-4-sulfonyl)-pyrrolidine-2-yl]-propylaminein accordance with the general method of example 6c yielded the titlecompound as a colorless oil, MS: m/e=325.4 (M+H⁺).

EXAMPLE 85(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole

[0308] The title compound, colorless oil, MS: m/e=428.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-imidazole.

EXAMPLE 86(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole

[0309] The title compound, colorless oil, MS: m/e=428.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-pyrazole.

EXAMPLE 87 (RS)-Cyclopropanecarboxylic acid{3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide

[0310] Acylation of(RS)-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamine (see examples33 and 87) according to the general method of example 6c yielded thetitle compound as a colorless oil, MS: m/e=351.3 (M+H⁺).

EXAMPLE 88(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2H-tetrazole

[0311] The title compound, colorless oil, MS: m/e=430.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 89(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-tetrazole

[0312] The title compound, colorless oil, MS: m/e=430.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 90(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-isobutyramide

[0313] Acylation of(2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamineaccording to the general method of example 6c yielded the title compoundas a colorless oil, MS: m/e=447.4 (M+H⁺).

EXAMPLE 91(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4-methyl-1H-imidazole

[0314] The title compound, colorless oil, MS: m/e=442.2 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 4-methyl-1H-imidazole.

EXAMPLE 92(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-1H-imidazole

[0315] The title compound, colorless oil, MS: m/e=442.2 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 2-methyl-1H-imidazole.

EXAMPLE 93(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-2H-tetrazole

[0316] The title compound, colorless oil, MS: m/e=444.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 94(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-1H-tetrazole

[0317] The title compound, colorless oil, MS: m/e=444.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 95(2RS,5SR)-3-Cyclopropyl-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,2,4]oxadiazole

[0318] The title compound, white solid, m.p. 102° C. and MS: m/e=442.3(M⁺), was prepared in accordance with the general method of example 13from N-hydroxy-cyclopropane-carboxamidine and(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid which was prepared by hydrolysis of(2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrile.

EXAMPLE 96(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-3-methyl-[1,2,4]oxadiazole

[0319] The title compound, white solid, m.p. 103° C. and MS: m/e=416.2(M⁺), was prepared in accordance with the general method of example 13from N-hydroxy-acetamidine and(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid.

EXAMPLE 97(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-1-methyl-1H-1,2,4]triazole

[0320] The title compound, light yellow oil, MS: m/e=415.1 (M+H⁺), wasprepared in accordance with the general method of example 26 from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetonitrileand methylhydrazine.

EXAMPLE 98(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethanol

[0321] Reduction of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid methyl ester, prepared by esterification of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid, with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueouswork-up and crystallization from EE/hexane yielded the title compound,white solid, m.p. 129° C. and MS: m/e=364.1 (M+H⁺).

EXAMPLE 99(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole

[0322] The title compound, colorless oil, MS: m/e=414.1 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,prepared from(2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethanolaccording to the general method of example 5, and 1H-imidazole.

EXAMPLE 100(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-pyrazole

[0323] The title compound, white solid, m.p.=121° C. and MS: m/e=414.2(M+H⁺), was prepared in accordance with the general method of example82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-pyrazole.

EXAMPLE 101(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2H-tetrazole

[0324] The title compound, colorless oil, MS: m/e=416.2 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 102(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-tetrazole

[0325] The title compound, colorless oil, MS: m/e=416.1 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 103(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-[1,2,4]triazole

[0326] The title compound, colorless oil, MS: m/e=415.1(M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-triazole.

EXAMPLE 104(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-2H-tetrazole

[0327] The title compound, colorless oil, MS: m/e=430.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 105(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-1H-tetrazole

[0328] The title compound, colorless oil, MS: m/e=430.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 106(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4-methyl-1H-imidazole

[0329] The title compound, light yellow oil, MS: m/e=428.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 4-methyl-1H-imidazole.

EXAMPLE 107(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-1H-imidazole

[0330] The title compound, light yellow oil, MS: m/e=428.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 4-methyl-1H-imidazole.

EXAMPLE 108(RS)-1-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole

[0331] a) (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanol

[0332] Reduction of(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methylester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueouswork-up and crystallization from diethyl ether/hexane yielded(RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanol, colorless oil,MS: m/e=284.2 (M+H⁺).

[0333] b)(RS)-1-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole

[0334] The title compound, colorless oil, MS: m/e=335.3 (M+H⁺), wasprepared in accordance with the general method of example 82b from(RS)-2-(3-chloro-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine, preparedfrom (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanol accordingto the general method of example 5, and 1H-triazole.

EXAMPLE 109(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole

[0335] a)(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-carboxaldehyde

[0336] Oxidation of(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olaccording to the general method of example 29a and purification of thecrude product by column cromatography on silica gel (ethylacetate/hexane 1:1) gave(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-carboxaldehydeas a light yellow oil.

[0337] b)(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole

[0338] To a cooled (0° C.) and stirred solution of(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-carboxaldehyde(1.30 g, 3.46 mmol) was added glyoxal (0.8 ml, 40% in water) andsubsequently ammonium hydroxide (1.15 ml, 25% in water). The reactionmixture was stirred 30 min at 0° C. and 15 h by RT, poured into water(30 ml) and extracted with dichloromethane (2×50 ml). The combinedorganic layers were washed with brine (30 ml), dried (MgSO₄) andevaporated. The crude product was purified by column chromatography onsilica gel (dichloromethane/methanol 19:1) to give the title compound(1.18 g, 82%) as a white foam, MS: m/e=414.3 (M+H⁺).

EXAMPLE 110(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole

[0339] The title compound, white foam, MS: m/e=428.5 (M+H⁺), wasprepared in accordance to the general method of example 109 from(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol.

EXAMPLE 111(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-imidazole

[0340] The title compound, light yellow oil, MS: m/e=428.5 (M+H⁺), wasprepared by methylation of(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazolein accordance with the general method of example 8 (methyl iodide,sodium hydride).

EXAMPLE 112(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-imidazole

[0341] The title compound, light yellow oil, MS: m/e=442.2 (M+H⁺), wasprepared by methylation of(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazolein accordance with the general method of example 8 (methyl iodide,sodium hydride).

EXAMPLE 113(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole

[0342] The title compound, white foam, MS: m/e=414.1 (M+H⁺) and [α]_(D)²⁰=96.93° (c=1.0399 in chloroform) was prepared from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-olin accordance with the general method of example 109.

EXAMPLE 114(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-imidazole

[0343] The title compound, light yellow oil, MS: m/e=428.2 (M+H⁺) and[α]_(D) ²⁰=−69.7° (c=0.2770 in chloroform), was prepared by methylationof(2R,5S)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazolein accordance with the general method of example 8 (methyl iodide,sodium hydride).

EXAMPLE 115(2R,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole

[0344] The title compound, colorless oil, MS: m/e=429.2 (M+H⁺) and[D]_(D) ²⁰=−73.1° (c=0.3011 in chloroform), was prepared in accordancewith the general method of example 82b from(2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,which was prepared from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanolaccording to the general method of example 5, and 1H-triazole.

EXAMPLE 116(2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole

[0345] The title compound, colorless oil, MS: m/e=428.5 (M+H⁺) and[α]_(D) ²⁰=−68.5° (c=0.3050 in chloroform), was prepared in accordancewith the general method of example 82b from(2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-imidazole.

EXAMPLE 117(2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole

[0346] The title compound, colorless oil, MS: m/e=428.5 (M+H⁺) and[α]_(D) ^(°)=−67.7° (c=0.2955 in chloroform), was prepared in accordancewith the general method of example 82b from(2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-pyrazole.

EXAMPLE 118(2R,5S)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0347] The title compound, colorless oil, MS: m/e=392.1 (M+H⁺) and[α]_(D) ²⁰=−82.7° (c=0.2682 in chloroform), was prepared in accordancewith the general method of example 8 from(2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.

EXAMPLE 119(2RS,5SR)-2-(2-Ethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0348] The title compound, light yellow oil, MS: m/e=392.2 (M+H⁺), wasprepared in accordance with the general method of example 8 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethan-1-oland ethyliodide.

EXAMPLE 120(2RS,5SR)-2-(2-Cyclopropylmethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0349] The title compound, light yellow oil, MS: m/e=418.3 (M+H⁺), wasprepared in accordance with the general method of example 8 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethan-1-oland cyclopropylmethylbromide.

EXAMPLE 121(2S,5S)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole

[0350] The title compound, colorless oil, MS: m/e=443.2 (M+H⁺) and[α]_(D) ²⁰=−68.8° (c=0.3443 in chloroform), was prepared in accordancewith the general method of example 26 from(2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrileand methylhydrazine.

EXAMPLE 122(2S,5R)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole

[0351] The title compound, colorless oil, MS: m/e=443.2 (M+H⁺) and[α]_(D) ²⁰=−53.7° (c=0.3929 in chloroform), was prepared in accordancewith the general method of example 26 from(2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrileand methylhydrazine.

EXAMPLE 123(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4,6-dimethyl-pyrimidine

[0352] a)(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine

[0353](2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine(1.1 g, 2.62 mmol) was dissolved in EtOH (50 ml) and acetic acid (5 ml)and hydrogenated on Ra—Ni at room temperature for 2 h. The catalyst wasfiltered off, the filtrate evaporated and the crude product crystallizedfrom saturated NaHCO₃ solution to give(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine(0.81 g, 76%) as a light brown solid.

[0354] b)(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4,6-dimethyl-pyrimidine

[0355] A stirred solution of(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine(0.35 g, 0.87 mmol) in pentan-2,4-dione (7 ml) was heated for 3 h at125° C. Evaporation and purification by column chromatography on silicagel (ethyl acetate) yielded the title compound (0.15 g, 38%) as a lightyellow oil, MS: m/e=468.3 (M+H⁺).

EXAMPLE 124(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4,6-dimethyl-pyrimidine

[0356] The title compound, light yellow oil, MS: m/e=454.3 (M+H⁺), wasprepared in accordance with the general method of example 123 b) from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-propionamidine.

EXAMPLE 125(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-pyrimidine

[0357] A stirred solution of(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine(0.33 g, 0.82 mmol) in 1,1,3,3-tetraethoxy-propane (7 ml) and DMF (1.5ml) was heated for 1 h at 150° C. Evaporation and purification by columnchromatography on silica gel (dichloromethane/MeOH 98:2) yielded thetitle compound (73 mg, 20%) as a light brown oil, MS: m/e=440.2 (M+H⁺).

EXAMPLE 126(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-pyrimidine

[0358] The title compound, light orange oil, MS: m/e=426.3 (M+H⁺), wasprepared in accordance with the general method of example 125 from(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-propionamidine.

EXAMPLE 127(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole

[0359] a)(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicAcid Hydrazide

[0360] To a stirred solution of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid methyl ester (1.5 g, 3.7 mmol) in MeOH (15 ml)was added hydrazinehydrate (0.54 ml, 11.1 mmol) and p-TsOH (10 mg) and the reaction mixturewas heated under reflux conditions for 24 h. Evaporation andpurification by column chromatography on silica gel(dichloromethane/MeOH 19:1) yielded(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid hydrazide (1.25 g, 83%) as a white solid.

[0361] b)(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole

[0362] A stirred solution of(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid hydrazide (0.4 g, 0.99 mmol) in triethyl orthoformiate (10 ml) washeated under reflux conditions for 13 h, evaporated and purified bycolumn chromato-graphy on silica gel (dichloromethane/MeOH 98:2).Further purification by crystallization from ethyl acetate/hexane gavethe title compound (276 mg, 67%) as an off-white solid, m.p.=138° C. andMS: m/e=416.3 (M+H⁺).

EXAMPLE 128(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole

[0363] The title compound, light yellow oil, MS: m/e=430.2 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid hydrazide and triethyl orthoacetate.

EXAMPLE 129(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-oxazole

[0364] A stirred mixture of(2RS,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionaldehyde(375 mg, 1.0 mmol, prepared from the corresponding alcohol by oxidationin accordance with the general method of example 29a),tosylmethyl-isocyanate (199 mg, 1.0 mmol), potassium carbonate (207 mg,1.5 mmol) and MeOH (10 ml) was heated under reflux conditions for 35 h,evaporated and purified by column chromato-graphy on silica gel (ethylacetate/hexane 4:1) to give the title compound (100 mg, 24%) as a lightyellow oil, MS: m/e=415.3 (M+H⁺).

EXAMPLE 130(2RS,5RS)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0365] The title compound, light yellow oil, MS: m/e=406.3 (M+H⁺), wasprepared in accordance with the general method of example 8 from(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-oland methyliodide.

EXAMPLE 131(2RS,5RS)-2-(4-Ethoxy-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0366] The title compound, colorless oil, MS: m/e=420.4 (M+H⁺), wasprepared in accordance with the general method of example 8 from(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-oland ethyliodide.

EXAMPLE 132(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-[1,3,4]oxadiazole

[0367] The title compound, light yellow oil, MS: m/e=430.1 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid hydrazide and triethyl orthoformiate.

EXAMPLE 133(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-[1,3,4]oxadiazole

[0368] The title compound, light yellow oil, MS: m/e=444.2 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid hydrazide and triethyl orthoacetate.

EXAMPLE 134(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole

[0369] The title compound, colorless oil, MS: m/e=443.3 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-triazole.

EXAMPLE 135(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-oxazole

[0370] The title compound, light yellow oil, MS: m/e=401.4 (M+H⁺), wasprepared in accordance with the general method of example 129 from(2RS,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-acetaldehydeand tosylmethyl-isocyanate.

EXAMPLE 136(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-pyrazole

[0371] The title compound, colorless oil, MS: m/e=442.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-pyrazole.

EXAMPLE 137(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,3,4]oxadiazole

[0372] The title compound, light yellow oil, MS: m/e=388.2 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid hydrazide and triethyl orthoformiate.

EXAMPLE 138(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,3,4]oxadiazole

[0373] The title compound, light yellow oil, MS: m/e=402.4 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid hydrazide and triethyl orthoformiate.

EXAMPLE 139(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole

[0374] The title compound, colorless oil, MS: m/e=442.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-imidazole.

EXAMPLE 140(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-4-methyl-1H-imidazole

[0375] The title compound, colorless oil, MS: m/e=456.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 4-methyl-1H-imidazole.

EXAMPLE 141(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,3,4]oxadiazole

[0376] The title compound, light yellow oil, MS: m/e=416.3 (M+H⁺), wasprepared in accordance with the general method of example 127 from(2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-aceticacid hydrazide and triethyl orthoacetate.

EXAMPLE 142(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol

[0377] Reduction of(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT,aqueous work-up and purification by column chromatography yielded thetitle compound as a colorless oil, MS: m/e=392.2 (M+H⁺).

EXAMPLE 143(2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2H-tetrazole

[0378] The title compound, colorless oil, MS: m/e=444.3 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 144(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-tetrazole

[0379] The title compound, colorless oil, MS: m/e=444.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 145(2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-2H-tetrazole

[0380] The title compound, pale yellow oil, MS: m/e=458.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 146(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-1H-tetrazole

[0381] The title compound, colorless oil, MS: m/e=458.4 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 5-methyl-1H-tetrazole.

EXAMPLE 147(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentan-1-ol

[0382] Reduction of(2RS,5RS)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoicacid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT,aqueous work-up and purification by column chromatography yielded thetitle compound as a light orange oil, MS: m/e 406.2 (M+H⁺).

EXAMPLE 148(2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-imidazole

[0383] The title compound, colorless oil, MS: m/e=456.5 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-pentyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-imidazole.

EXAMPLE 149(2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-[1,2,4]triazole

[0384] The title compound, colorless oil, MS: m/e=457.1 (M+H⁺), wasprepared in accordance with the general method of example 82b from(2RS,5RS)-2-(4-chloro-pentyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-triazole.

EXAMPLE 150(2S,5S)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol

[0385] Reduction of(2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyricacid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT,aqueous work-up and purification by column chromatography yielded thetitle compound as a colorless oil, MS: m/e=392.3 (M+H⁺) and [α]_(D)²⁰=−80.1° (c=1.0870 in chloroform).

EXAMPLE 151(2S,5S)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine

[0386] The title compound, colorless oil, MS: m/e=406.1 (M+H⁺) and[α]_(D) ²⁰=−76.2° (c=0.2558 in chloroform), was prepared in accordancewith the general method of example 8 from(2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-oland methyliodide.

EXAMPLE 152(2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole

[0387] The title compound, colorless oil, MS: m/e=442.3 (M+H⁺) and[α]D²⁰=−64.3° (c=0.2673 in chloroform), was prepared in accordance withthe general method of example 82b from(2S,5S)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-imidazole.

EXAMPLE 153(2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole

[0388] The title compound, colorless oil, MS: m/e=443.3 (M+H⁺) and[α]_(D) ²⁰=−72.5° (c=0.2358 in chloroform), was prepared in accordancewith the general method of example 82b from(2S,5S)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidineand 1H-tetrazole.

EXAMPLE 154(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole

[0389] The title compound, light yellow oil, MS: m/e=416.1 (M+H⁺) and[α]_(D) ²⁰=−80.1° (c=0.2211 in chloroform), was prepared in accordancewith the general method of example 127 from(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionicacid hydrazide and triethyl orthoformiate.

EXAMPLE A

[0390] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 100 Powdered. lactose95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10Magnesium stearate 2 Tablet weight 250

EXAMPLE B

[0391] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 200 Powdered. lactose100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch20 Magnesium stearate 4 Tablet weight 400

EXAMPLE C

[0392] Capsules of the following composition are produced: mg/CapsuleActive ingredient 50 Crystalline. lactose 60 Microcrystalline cellulose34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

[0393] The active ingredient having a suitable particle size, thecrystalline lactose and the microcrystalline cellulose are homogeneouslymixed with one another, sieved and thereafter talc and magnesiumstearate are admixed. The final mixture is filled into hard gelatinecapsules of suitable size.

1. A compound of the formula

wherein R¹ is hydrogen or aryl, which is unsubstituted or substituted byhalogen; R² is aryl, which is unsubstituted or substituted by halogen orlower alkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 n or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or pharmaceuticallyacceptable salts thereof:
 2. A compound according to claim 1 wherein R¹is hydrogen; R² is phenyl unsubstituted or substituted by halogen orlower alkyl; R³ and n are as defined above.
 3. A compound according toclaim 2 wherein R² is p-tolyl and n is
 3. 4. A compound according toclaim 3 wherein R³ is N(R′)—C(O)—R⁴, or a 5- or 6-membered heteroarylring containing from 1 to 4 N or O heteroatoms, said ring beingunsubstituted or substituted by lower alkyl or cycloalkyl, and R⁴ is asdefined above.
 5. The compound of claim 4, which is(RS)-N-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide. 6.The compound of claim 4, which is (RS)-Cyclopropanecarboxylic acid{3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.
 7. Thecompound of claim 4, which is(RS)-1-{3-[1-(Toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.8. A compound according to claim 1 wherein R¹ is phenyl or halosubstituted phenyl and R² is phenyl, or halo substituted phenyl or loweralkyl substituted phenyl.
 9. A compound according to claim 1 having thestructure

wherein R³ and n are as defined above; and wherein R⁵ is hydrogen,halogen or lower alkyl.
 10. A compound according to claim 9 wherein R³is —OR′, N-hydroxy-amidino, —C(O)NR′R″ or —N(R′)—C(O)—R⁴; R⁵ is halogenand n is 2 or
 3. 11. The compound of claim 10, which is(2RS,5SR)-N-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-acetamide.12. The compound of claim 10, which is (2RS,5SR)-Cyclopropanecarboxylicacid{2-[1-(4-chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-amide.13. The compound of claim 10, which is(2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propionamide.14. The compound of claim 10, which is(2RS,5RS)-N-{3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propyl}-acetamide.15. The compound of claim 10, which is(2RS,5SR)-3-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-propan-1-ol.16. The compound of claim 10, which is(2RS,5SR)-5-{2-[1-(4-Chloro-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.17. A compound according to claim 9 wherein R³ is OR′, R⁵ is ethyl, R′is as defined above and n is
 1. 18. The compound of claim 17, which is(2RS,5SR)-[1-(4-Ethyl-benzenesulfonyl)-5-(4-fluoro-phenyl)-pyrrolidin-2-yl]-methanol.19. A compound according to claim 9 having the structure

wherein R³ and n are as defined above.
 20. A compound according to claim19 wherein R³ is an unsubstituted 5-membered heteroaryl ring containing1 to 4 from N or O heteroatoms.
 21. A compound according to claim 20wherein said unsubstituted 5-membered heteroaryl ring contains from 1 to4 nitrogen atoms and n is 0, 1 or
 2. 22. The compound of claim 21, whichis(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.23. The compound of claim 21, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-pyrazole.24. The compound of claim 21, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2H-tetrazole.25. The compound of claim 21, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-tetrazole.26. The compound of claim 21, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-[1,2,4]triazole.27. A compound according to claim 20 wherein said heteroaryl ringincludes at least one oxygen atom and n is 0, 1 or
 2. 28. The compoundof claim 27, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,2,4]oxadiazole.29. The compound of claim 27, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole.30. The compound of claim 27, which is(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-oxazole.31. The compound of claim 27, which is(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-oxazole.32. The compound of claim 27, which is(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-[1,3,4]oxadiazole.33. A compound according to claim 20 wherein said unsubstituted5-membered heteroaryl ring contains from 1 to 4 nitrogen atoms and n is3, 4 or
 5. 34. The compound of claim 33, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.35. The compound of claim 33, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.36. The compound of claim 33, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole.37. The compound of claim 33, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2H-tetrazole.38. The compound of claim 33, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-tetrazole.39. The compound of claim 33, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-pyrazole.40. The compound of claim 33, which is(2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2H-tetrazole.41. The compound of claim 33, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-tetrazole.42. The compound of claim 33, which is(2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-imidazole.43. The compound of claim 33, which is(2RS,5RS)-1-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-1H-[1,2,4]triazole.44. The compound of claim 33, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole.45. The compound of claim 33, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.
 46. A compoundaccording to claim 19 wherein R³ is a substituted 5-membered heteroarylring containing from 1 to 4 N or O heteroatoms.
 47. A compound accordingto claim 46 wherein said substituted 5-membered heteroaryl ring containsfrom 1 to 4 nitrogen atoms and n is 0, 1 or
 2. 48. The compound of claim47, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-[1,2,4]triazole.49. The compound of claim 47, which is(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2-methyl-2H-tetrazole.50. The compound of claim 47, which is(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H-tetrazole.51. The compound of claim 47, which is(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.52. The compound of claim 47, which is(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole.53. The compound of claim 47, which is(2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole.54. The compound of claim 47, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-1-methyl-1H-[1,2,4]triazole.55. The compound of claim 47, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-2H-tetrazole.56. The compound of claim 47, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-1H-tetrazole.57. The compound of claim 47, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4-methyl-1H-imidazole.58. The compound of claim 47, which is(2RS,5SR)-1-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-1H-imidazole.59. A compound according to claim 46 wherein said substituted 5-memberedheteroaryl ring contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5.60. The compound of claim 59, which is(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-2H-tetrazole.61. The compound of claim 59, which is(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-tetrazole.62. The compound of claim 59, which is(2RS,5RS)-5-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1-methyl-1H-tetrazole.63. The compound of claim 59, which is(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.64. The compound of claim 59, which is(2RS,5RS)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.65. The compound of claim 59, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4-methyl-1H-imidazole.66. The compound of claim 59, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-1H-imidazole.67. The compound of claim 59, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-2H-tetrazole.68. The compound of claim 59, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-1H-tetrazole.69. The compound of claim 59, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-4-methyl-1H-imidazole.70. The compound of claim 59, which is(2RS,5RS)-2-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-2H-tetrazole.71. The compound of claim 59, which is(2RS,5RS)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-5-methyl-1H-tetrazole.72. A compound according to claim 19 wherein R³ is a substituted5-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms andcontaining at least one N atom and at least one O atom.
 73. A compoundaccording to claim 72 wherein n is 0, 1 or
 2. 74. The compound of claim73, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-[1,2,4]oxadiazole.75. The compound of claim 73, which is(2RS,5SR)-5-Phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acidamide.
 76. The compound of claim 73, which is(2RS,5SR)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-3-methyl-[1,2,4]oxadiazole.77. The compound of claim 73, which is(2RS,5SR)-5-Cyclopropyl-3-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole.78. The compound of claim 73, which is(2RS,5SR)-3-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,2,4]oxadiazole.79. The compound of claim 73, which is(2RS,5SR)-3-Cyclopropyl-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,2,4]oxadiazole.80. The compound of claim 73, which is(2RS,5SR)-3-Cyclopropyl-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,2,4]oxadiazole.81. The compound of claim 73, which is(2RS,5SR)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-3-methyl-[1,2,4]oxadiazole.82. The compound of claim 73, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-5-methyl-[1,3,4]oxadiazole.83. The compound of claim 73, which is(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,3,4]oxadiazole.84. A compound according to claim 72 wherein n is 3, 4 or
 5. 85. Thecompound of claim 84, which is(2RS,5RS)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-[1,2,4]oxadiazole.86. The compound of claim 84, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-[1,3,4]oxadiazole.87. A compound according to claim 19 wherein R³ is an unsubstituted5-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms andcontaining at least one N atom and one O atom and wherein n is 3, 4 or5.
 88. The compound of claim 87, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-[1,3,4]oxadiazole.89. A compound according to claim 19 wherein R³ is —C(O)—OR.
 90. Thecompound of claim 89, which is(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester.
 91. A compound according to claim 19 wherein R³ is—OR′.
 92. The compound of claim 91, which is(2RS,5SR)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol.93. The compound of claim 91, which is(2RS,5SR)-2-(4-Fluoro-phenyl)-5-methoxymethyl-1-(toluene-4-sulfonyl)-pyrrolidine.94. The compound of claim 91, which is(2RS,5RS)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.95. The compound of claim 91, which is(2RS,5SR)-2-(4-Fluoro-phenyl)-5-(2-methoxy-ethyl)-1-(toluene-4-sulfonyl)-pyrrolidine.96. The compound of claim 91, which is(2RS,5RS)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine.97. The compound of claim 91, which is(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethanol.98. The compound of claim 91, which is(2RS,5RS)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.99. The compound of claim 91, which is(2RS,5RS)-2-(4-Ethoxy-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.100. The compound of claim 91, which is(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol.101. The compound of claim 91, which is(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentan-1-ol.102. A compound according to claim 19 wherein R³ is —C(O)NR′R″.
 103. Thecompound of claim 102, which is(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid amide.
 104. The compound of claim 102, which is(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid (pyridin-3-yl-methyl)-amide hydrochloride.
 105. The compound ofclaim 102, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.106. The compound of claim 102, which is(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoicacid amide.
 107. The compound of claim 102, which is(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyramide.108. A compound according to claim 19 wherein R³ is N-hydroxy-amidino.109. The compound of claim 108, which is(2RS,5SR)-5-(4-Fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine.110. The compound of claim 108, which is(2RS,5SR)-2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine.111. The compound of claim 108, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-propionamidine.112. The compound of claim 108, which is(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine.113. The compound of claim 108, which is(2RS,5RS)-5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-pentanamidine.114. A compound according to claim 19 wherein R³ is —N(R′)—C(O)—R⁴. 115.The compound of claim 114, which is(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-propionamide.116. The compound of claim 114, which is(2RS,5SR)-Cyclopropanecarboxylic acid[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide.117. The compound of claim 114, which is(2SR,5SR)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.118. The compound of claim 114, which is(2SR,5SR)-Cyclopropanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.119. The compound of claim 114, which is(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-propionamide.120. The compound of claim 114, which is(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2,2-dimethyl-propionamide.121. The compound of claim 114, which is(2RS,5RS)-Cyclopentanecarboxylic acid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.122. The compound of claim 114, which is(2RS,5RS)-N-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-acetamide.123. The compound of claim 114, which is(2RS,5RS)-Cyclopropanecarboxylic acid{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-amide.124. The compound of claim 114, which is(2RS,5RS)-N-{5-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-acetamide.125. The compound of claim 114, which is(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-benzamide.126. The compound of claim 114, which is(2RS,5RS)-2,2,2-Trifluoro-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.127. The compound of claim 114, which is(2RS,5RS)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-isobutyramide.128. The compound of claim 114, which is(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-acetamide.129. A compound according to claim 19 wherein R³ is —C(O)—OR.
 130. Thecompound of claim 129, which is(2RS,5SR)-5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylicacid methyl ester.
 131. A compound according to claim 19 wherein R³ is—N(R′)—C(S)—NR′R″ and R′ and R′″ are as defined above.
 132. The compoundof claim 131, which is(2RS,5RS)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-3-methyl-thiourea.133. A compound according to claim 19 wherein R³ is an unsubstituted6-membered heteroaryl ring containing 2 nitrogen atoms.
 134. Thecompound of claim 133, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-pyrimidine.135. The compound of claim 133, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-pyrimidine.136. A compound according to claim 19 wherein R³ is a substituted6-membered heteroaryl ring containing 2 nitrogen atoms.
 137. Thecompound of claim 136, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-4,6-dimethyl-pyrimidine.138. The compound of claim 136, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-4,6-dimethyl-pyrimidine.139. A compound according to claim 9 wherein R³ is a dihydro derivativeof a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or Oheteroatoms, which are unsubsituted or substituted by lower alkyl orcycloalkyl; and n is an integer from 0 to
 5. 140. The compound of claim139, which is3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-5-methyl-4,5-dihydro-[1,2,4]oxadiazole.141. A compound according to claim 1 having the structure

wherein R³ and n are as defined above.
 142. A compound according toclaim 141 wherein R³ is —N(R′)—C(O)—R⁴, R⁴ and R′ are as defined above,and n is 0, 1 or
 2. 143. The compound of claim 142, which is(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-propionamide.144. The compound of claim 142, which is(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-benzamide.145. The compound of claim 142, which is(2RS,5SR)-Cyclopropanecarboxylic acid{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-amide.146. The compound of claim 142, which is(2RS,5SR)-N-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-acetamide.147. The compound of claim 142, which is(2RS,5SR)-Cyclopentanecarboxylic acid[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide.148. The compound of claim 142, which is(2RS,5SR)-N-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2,2-dimethyl-propionamide.149. The compound of claim 142, which is(2R,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.150. A compound according to claim 141 wherein R³ is —N(R′)—C(O)—R⁴;wherein R⁴ and R′ are as defined above; and wherein n is 3, 4 or
 5. 151.The compound of claim 150, which is(2S,5S)-N-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide.152. The compound of claim 150, which is (2S,5S)-Cyclopropane-carboxylicacid{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide.153. A compound according to claim 151 wherein R³ is —C(O)NR′R″ and R′and R″ are as defined above.
 154. The compound of claim 153, which is(2RS,5SR)-5-Phenyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acidamide.
 155. The compound of claim 153, which is(2R,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.156. A compound according to claim 141 wherein R³ is a 5- or 6-memberedheteroaryl ring containing from 1 to 4 N or O heteroatoms, said ringbeing unsubstituted or substituted by lower alkyl or cycloalkyl.
 157. Acompound according to claim 156 wherein R³ is a substituted 5-memberedheteroaryl ring and n is 0, 1 or
 2. 158. The compound of claim 157,which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-5-methyl-[1,2,4]oxadiazole.159. The compound of claim 157, which is(2RS,5SR)-5-Cyclopropyl-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole.160. The compound of claim 157, which is(2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole.161. The compound of claim 157, which is(2R,5S)-5-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole.162. The compound of claim 157, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-11-methyl-1H-imidazole.163. The compound of claim 157, which is(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-imidazole.164. A compound according to claim 156 wherein R³ is a substituted5-membered heteroaryl ring and n is 3, 4 or
 5. 165. The compound ofclaim 164, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-imidazole.166. The compound of claim 164, which is(2S,5S)-5-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.167. The compound of claim 164, which is(2S,5R)-3-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole.168. A compound according to claim 156 wherein R³ is an unsubstituted5-membered heteroaryl ring and n is 0, 1 or
 2. 169. The compound ofclaim 168, which is(2RS,5SR)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-[1,2,4]oxadiazole.170. The compound of claim 168, which is(2RS,5SR)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.171. The compound of claim 168, which is(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole.172. The compound of claim 168, which is(2R,5S)-2-{2-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole.173. A compound according to claim 156 wherein R³ is an unsubstituted5-membered heteroaryl ring and n is 3, 4 or
 5. 174. The compound ofclaim 173, which is(2RS,5RS)-2-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.175. The compound of claim 173, which is(2R,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole.176. The compound of claim 173, which is(2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole.177. The compound of claim 173, which is(2S,5S)-1-{3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole.178. The compound of claim 173, which is(2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-imidazole.179. The compound of claim 173, which is(2S,5S)-1-{4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.180. A compound according to claim 141 wherein R³ is —OR′, R′ is asdefined above, and n is 0, 1 or
 2. 181. The compound of claim 180, whichis(2R,5S)-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol.182. The compound of claim 180, which is(2RS,5SR)-2-(2-Ethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.183. The compound of claim 180, which is(2RS,5SR)-2-(2-Cyclopropylmethoxy-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine.184. A compound according to claim 141 wherein R³ is —OR′, R′ is asdefined above, and n is 3, 4 or
 5. 185. The compound of claim 184, whichis(2S,5S)-3-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.186. The compound of claim 184, which is(2R,5S)-2-(4-Fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine.187. The compound of claim 184, which is(2S,5S)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol.188. The compound of claim 184, which is(2S,5S)-2-(4-Fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.189. A method of treating a person having a disease state treatable bymodulation of the metabotropic glutamate receptor comprisingadministering, to a person in need of such treatment, an effectiveamount of a compound of the formula

wherein R¹ signifies hydrogen or aryl, which is unsubstituted orsubstituted by halogen; R² signifies aryl, which is unsubstituted orsubstituted by halogen or lower alkyl; R³ signifies —OR′,N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″, —N(R′)—C(O)—R⁴,—N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ring containing from1 to 4 N or O heteroatoms, said ring being unsubstituted or substitutedby lower alkyl or cycloalkyl; R⁴ signifies cycloalkyl, phenyl or loweralkyl, which is unsubstituted or substituted by halogen; R signifieslower alkyl; R′ and R′″ signify hydrogen, lower alkyl orcycloalkyl-lower alkyl; R″ signifies hydrogen, lower alkyl or loweralkyl substituted by a 5- or 6-membered heteroaryl ring containing from1 to 4 N or O heteroatoms, said ring being unsubstituted or substitutedby lower alkyl or cycloalkyl, and n is an integer from 0 to 5; or apharmaceutically acceptable salt thereof.
 190. A method of treatmentaccording to claim 189, further comprising administering a medicamentwhich comprises an effective amount of the compound of formula I in asuitable pharmaceutical vehicle for the control or prevention of acuteand/or chronic neurological disorders selected from the group consistingof restricted brain function caused by bypass operations or transplants,poor blood supply to the brain, spinal cord injuries, head injuries,hypoxia caused by pregnancy, cardiac arrest, hypoglycaemia, Alzheimer'sdisease, Huntington's chorea, ALS, dementia caused by AIDS, eyeinjuries, retinopathy, cognitive disorders, memory deficits, acute andchronic pain, schizophrenia, idiopathic parkinsonism or parkinsonismcaused by medicaments, and conditions which lead to glutamate deficiencyfunctions.
 191. A method of treatment according to claim 190 wherein theacute and/or chronic neurological disorder is selected from the groupconsisting of muscle spasms, convulsions, migraine, urinaryincontinence, nicotine addiction, psychoses, opiate addiction, anxiety,vomiting, dyskinesia and depression.
 192. A method of treatmentaccording to claim 190, further comprising administering to the patientin need of treatment a sufficient amount of said medicament to modulatethe metabotropic glutamate receptors mGluR1 and mGluR5, thereby treatingthe disease state in the patient.
 193. A medicament comprising acompound of formula I or a pharmaceutically acceptable salt thereof; andat least one pharmaceutically acceptable excipient.
 194. A process forthe manufacture of a compound of formula I or a pharmaceuticallyacceptable salt thereof, which process comprises reacting a compound ofthe formula

with a compound of formula

to obtain a compound of formula

or, converting a functional group of R³ in a compound of formula I intoanother functional group, or, converting a compound of formula I into apharmaceutically acceptable salt.
 195. The compound according to claim 1having the following formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 196. A compound according to claim 1 having thefollowing formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 197. A compound according to claim 1 having thefollowing formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 198. A compound according to claim 1 having thefollowing formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 199. A compound according to claim 1 having thefollowing formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 200. A compound according to claim 1 having thefollowing formula

wherein R¹ is aryl, which is unsubstituted or substituted by halogen; R²is aryl, which is unsubstituted or substituted by halogen or loweralkyl; R³ is —OR′, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″,—N(R′)—C(O)—R⁴, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ringcontaining from 1 to 4 N or O heteroatoms, said ring being unsubstitutedor substituted by lower alkyl or cycloalkyl; R⁴ is cycloalkyl, phenyl orlower alkyl, which is unsubstituted or substituted by halogen R is loweralkyl; R′ and R′″ are hydrogen, lower alkyl or cycloalkyl-lower alkyl;R″ is hydrogen, lower alkyl or lower alkyl substituted by a 5- or6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms,said ring being unsubstituted or substituted by lower alkyl orcycloalkyl, and n is an integer from 0 to 5; or a pharmaceuticallyacceptable salt thereof.
 201. A compound according to claim 1 wherein R³is imidazole, pyrazole, [1.2.4]triazole, [1.2.4]oxadiazole, tetrazole,[1.3.4]oxadiazole or oxazole.
 202. A compound according to claim 1wherein R³ is —N(R′)—C(O)—R⁴.